Introduction
Atopic dermatitis (AD) is one of the most common chronic inflammatory
dermatoses, occurring often in families with atopic predisposition and
other atopic diseases (1). Pruritus and eczematous lesions are important
clinical manifestations of AD, with pruritus being the most debilitating
symptom of the disease (2-4). The distribution and morphology of the
lesions vary with age, and especially during infancy sensitive skin
areas, such as the face, neck, and scalp, are affected (1, 5). Although
the pathophysiology of AD is not completely understood, accumulating
evidence suggests a complex interplay between genetic, immunological,
and environmental factors contributing to impaired epidermal barrier
function and allergic inflammation (1, 5-8). The worldwide prevalence of
AD ranges between 10 and 20% in the pediatric population, depending on
the geographic region (9, 10). Among patients with AD, the majority have
an onset in infancy, with about 73% presenting symptoms before the age
of 2 years, underscoring the importance of early effective and safe
management in the infant age group (7, 11, 12). Furthermore, persistence
of AD is prolonged with age of onset, as patients who were diagnosed
between the ages of 0 to 1 year or between the ages of 6 to 11 years had
a median persistence of AD of 3 or 12.5 years, respectively (13).
Currently, AD cannot be cured and management focuses on restoring the
disturbed epidermal barrier function and tempering the inflammatory skin
responses, to ultimately treat and reduce the risk of flares on the
long-term (14). The recently published consensus-based European
guidelines for treatment of AD, recommend topical corticosteroids (TCS)
as first-line anti-inflammatory therapy in infants with mild-to-moderate
AD (14). However, TCS are associated with several limitations due to
potential local side effects, including skin infections, impairment of
the epidermal barrier function, and skin atrophy, which limit their use
for treatment of sensitive skin areas (14, 15). Additionally,
percutaneous absorption of TCS through the disrupted skin may lead to
systemic exposure and subsequent growth impairment (15). As a result of
these safety limitations, adherence to TCS is often poor due to
corticophobia (14, 16). The topical calcineurin inhibitors (TCIs) –
pimecrolimus 1% cream (Elidel®, Meda, Stockholm,
Sweden) and tacrolimus 0.03% and 0.1% ointment
(Protopic®, Astellas, Tokyo, Japan) – are another
class of anti-inflammatory drugs, which are indicated for
mild-to-moderate and moderate-to-severe AD, respectively (17-20). TCIs
have a more selective mechanism of action compared to TCS and do not
cause impairment of the epidermal barrier function and skin atrophy (14,
21, 22). Therefore, the European guidelines for treatment of AD
recommend TCIs for use in sensitive skin areas as well as for long-term
treatment (14). Evidence from clinical trials on the use of TCIs for the
treatment of AD in infants mostly exists for pimecrolimus. Based on this
evidence, pimecrolimus is approved in infants aged ≥3 months in 10
countries (Elidel® [pimecrolimus] cream 1%,
Prescribing Information [Australia, Brazil, Canada, India, Indonesia,
Israel, New Zealand, Philippines, Russia, and Thailand]). However,
pimecrolimus is currently not approved in Europe and the United States
(US) in children below the age of 2 years due to initial safety
concerns. In 2006, the Food & Drug Administration (FDA) added a
black-box warning to the TCIs labels to emphasize that long-term use has
not been established, warning about a theoretical increased risk of
lymphoma and skin malignancies, and indicating that use of TCIs in
infants is not approved (17). In the same year, the European Medicines
Agency (EMA) limited the use of TCIs to second-line treatment of AD
following a safety review (18). During the last 20 years, both the
short- and long-term safety of pimecrolimus for the treatment of AD in
infants has been extensively evaluated. Furthermore, a previous
recommendation from an international group of dermatologists already
concluded in 2015 that use of pimecrolimus should no longer be
restricted to children above the age of 2 years (23). This review aims
to provide the rationale behind the high need to initiate treatment of
AD during infancy and to update the previous consensus guidance on the
use of pimecrolimus in infants between 3 months and 2 years of age.